Aerosolized medicines are frequently used to treat individuals suffering from respiratory disease. The inhalation of aerosols is an effective approach to deliver therapeutic concentrations of medicines directly to the site of disease (e.g. the airways). Nebulizer devices, such as jet nebulizers, are commonly used to generate respirable aerosol particles (e.g. particles that are <10 mm in diameter) from liquid medication. Examples of Jet Nebulizers include the Pari LC Star and Pari LC Plus which often require 10-20 minutes to deliver a single dose of medication. For subjects with chronic pulmonary disease whom may require multiple daily aerosol treatments, the time burden associated with drug delivery via Jet nebulizers can become substantial (e.g. more than 2 or more hours per day dedicated to aerosol therapy). As an example of such therapy, Elkins et al., N Engl J. Med, 354(3):229-40(2006) showed that delivering 4 ml of 7% hypertonic saline twice a day via Pari LC Plus jet nebulizer to CF patients during their waking hours leads to a decreased rate of pulmonary exacerbations and modest improvement in lung function. At the same time, this treatment adds 30+ minutes spent on treatment per day. Similarly, Ramsey et al., N Engl J Med, 340(1):23-30 (1999) demonstrated that administering 5 ml of sterile tobramycin antibiotic solution via Pari LC PLUS jet nebulizer to CF patients during their waking hours leads to a decreased rate of pulmonary exacerbations and an improvement in lung function. At the same time, this treatment adds 40+ minutes spent on treatment per day.
One strategy to improve the time burden associated with aerosol therapy is via the delivery of medicines by newer, more efficient nebulizer devices. The current state-of-the-art in pulmonary medicine is the delivery of aerosolized medicines more rapidly and efficiently to the airways. The primary goal of these high-efficiency nebulizer systems is to reduce the drug delivery time and minimize the time burden on the patient. Examples of these devices include vibrating mesh nebulizers such as the PARI EFLOW™ nebulizer and the AEROGEN PRONEB™ nebulizer (operating parameters shown in Table 1). Vibrating mesh nebulizers are capable of delivering a dose of an inhaled agent comparable to a jet nebulizer in approximately half the time. The time saving stemming from the more efficient vibrating nebulizers is important for respiratory diseases where patients are exposed to a large treatment burden. Another example of such devices are metered dose inhalers and dry powder inhalers. While these devices have some limitations related to maximum deliverable dose and tolerability compared to nebulizers, they offer additional convenience to the patients via further reduced drug delivery times.
However, time saving due to the use of high-efficiency nebulizers may not be sufficient for respiratory diseases such as cystic fibrosis where patients are often required to take combination of several inhaled treatments, oral treatments, physiotherapy and exercise. It is not uncommon for CF patients to spend 2-3 hours per day on treatments that are recommended by treatment guidelines (Flume et al., Am J Respir Crit Care Med. 2007 Nov. 15; 176(10):957-69; Sawicki et al., J Cyst Fibros. 2009 March; 8(2):91-6). The treatment burden due to this extensive treatment regimen is so large that adding another inhaled treatment during patient's waking hours often leads to displacement of the other treatments or decreased compliance. For this reason, administration of inhaled treatments during patients sleeping hours may be beneficial as it does not contribute to the treatment burden experienced by these patients during the waking hours. Similarly, such overnight aerosol delivery may result in improved compliance associated with improved efficacy of both the overnight treatment and the daily treatments, compared to adding another inhaled treatment to existing treatment regimen.
The most commonly used nebulizer devices (including jet and vibrating mesh nebulizers) deliver aerosolized medicines to patients as concentrated “boluses” over a short time period (e.g. 5 to 20 minutes per treatment). These boluses lead to a rapid increase of the active therapeutic agent in lumen of the lung and the surrounding tissues, often above the necessary therapeutic concentration for a short period of time. Similarly, these boluses lead to systemic exposure to such agents. These peak local and systemic concentrations following bolus administrations of inhaled aerosols can lead to undesirable safety and tolerability profiles which may prevent adoption of the therapy into the standard of care. For example, chronic inhaled corticosteroids have been shown to have disease-modifying impact on the rate of lung function decline in CF (Ren et al., J Pediatr., 153(6):746-5I (2008), de Boeck et al., Eur Respir J., 37(5):1091-5 (2011)) but are accompanied by patients' decreased linear growth, and increased insulin/oral hypoglycemic use due to the systemic exposure. As such, inhaled corticosteroids are not recommended for general treatment of CF lung disease (Flume et al., Am J Respir Crit Care Med. 2007 Nov. 15; 176(10):957-69).
The most commonly used nebulizer devices (including jet and vibrating mesh nebulizers) deliver aerosolized medicines to patients as concentrated “boluses” over a short time period (e.g. 5 to 20 minutes per treatment). However, for many medications “bolus” aerosol delivery is not optimal.
The present invention can address previous shortcomings in the art by providing methods, compositions and apparatus for administering active agents to the lungs of a subject.